During embryonic development, undifferentiated neuroepithelial cells proliferate and give rise to the enormous variety of neurons that populate the CNS. During their development, young cerebral cortical neurons must make many choices about where to migrate, what layer to sit in, and what kind of axonal connections to form. The goal of my research program is to begin to identify the cellular and molecular processes by which young neurons in the developing visual cortex achieve their normal fates. Four sets of issues are under study: (1) When are the axonal projection patterns and neurochemical phenotypes of cortical neurons determined during development? We will use transplantation experiments to determine when neurons become committed to forming layer-specific patterns of axonal connection, and whether neurons capable of altering their normal fates have a restricted neurochemical phenotype. (2) What signalling mechanisms are in involved in deep-layer fate determination? We will ask whether young progenitor cells require cell-cell interactions to make commitments to generating neurons destined for the deep layers of the cortex, or whether this fate serves as a "default pathway" that is acquired in the absence of active extracellular signals. Should cell- cell interactions be required for fate determination, we will explore the possible sources of such signals by attempting to reconstitute the signalling process in vitro. (3) Do late cortical precursors have a more restricted developmental potential than early precursors? Late in development, cortical progenitor cells normally give rise only to upper- layer neurons. We will use transplantation techniques to address the issue of whether the developmental potential of late cortical progenitors is comparable to or more restricted than that of early multipotent progenitors, by asking whether late precursor cells are capable of generating deep-layer neurons. (4) What molecules may be involved in laminar determination and layer formation? We have identified three molecules that are differentially expressed in upper- and deep-layer cortical neurons, two of which are homeodomain genes that might conceivably play a role in the determination of laminar fates. We will characterize the pattern of expression of these molecules during development, and ask whether their expression is cell-autonomous or inducible by cell-cell interactions in vitro. The results of these should contribute to our understanding of the cellular and molecular basis of neuronal migration and the formation of specific connections in the visual system. Furthermore, they may suggest new strategies for the treatment of developmental brain disorders in humans, in which neuronal migration or specific synapse formation has gone awry.